Migrastatin Analogues Inhibit Canine Mammary Cancer Cell Migration and Invasion

Kinga Majchrzak,Agata Homa,Tomasz Motyl,Paul V Murphy,Karol Pawłowski,Małgorzata Gajewska,Magdalena Król,Małgorzata Bulkowska,Daniele Lo Re,Waldemar Debinski

doi:10.1371/journal.pone.0076789

Kinga Majchrzak, Agata Homa + Show 8 more

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https://doi.org/10.1371/journal.pone.0076789

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Abstract

BackgroundCancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6) on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer.ResultsOur results showed that two of six fully synthetic analogues of migrastatin: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6) disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion.ConclusionTwo synthetic migrastatin analogues (MGSTA-5 and MGSTA-6) were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs. However, further in vivo studies are required to verify this hypothesis.

Highlights

Metastasis is the cause of most cancer deaths [1,2]
Previous studies conducted on human A549 lung cancer cell line demonstrated that lower concentrations of migrastatin analogues (ME - migrastatin core ether) did not affect cell migration [13]
In order to determine the mechanism of action of the most potent migrastatin analogue MGST-6 in canine mammary cancer cells we examined the phenotype of the those cells cultured on reconstituted basement membrane (MatrigelTM Matrix) in the presence of migrastatin 6 (MGSTA-6) at 100 μM (Figure 6)

Summary

Introduction

Metastasis is the cause of most cancer deaths [1,2]. it is extensively investigated, it still remains one of the most inscrutable aspects of the disease. The aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6) on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Results: Our results showed that two of six fully synthetic analogues of migrastatin: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. Conclusion: Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6) were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs. Further in vivo studies are required to verify this hypothesis

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